Genetic mutation and aqueous humor metabolites alterations in a family with Marfan syndrome.

This study used four generations of a Chinese family to reveal the genetic etiology and ocular manifestation pathogenesis of Marfan syndrome (MFS) through whole genome sequencing (WGS) and metabolomics analysis. In the study, we explored the pathogenic gene variant and aqueous humor (AH) metabolites alterations of MFS. Using WGS, a novel heterozygous variant (NM_000138: c.G4192A, p.D1398 N) in the fibrilin-1 ( gene was identified. This variant was co-segregated with the phenotype and considered "deleterious" and highly conserved during evolution. The p.D1398 N variant is located in a cbEGF-like domain and predicted to lead to a new splice site, which might result in structural and functional changes to the FBN1 protein. is highly expressed in the mouse cornea, conjunctiva and lens capsule, which highlights the important role of FBN1 in eyeball development. AH metabolomics analysis identified eight differentially expressed metabolites, including 3-hydroxyphenylacetic acid, 4-pyridoxic acid, aminoadipic acid, azelaic acid, chlordiazepoxide, niacinamide, ribose, 1,5-bisphosphate and se-methylselenocysteine, associated with relevant metabolic pathways likely involved in the pathogenesis of ocular symptoms in MFS. Our analysis extends the existing spectrum of disease-causing mutations and reveals metabolites information related to the ophthalmic features of MFS. This may provide a new sight and a basis for the diagnosis and mechanism of MFS.